| Abstract: |
Purpose: Pertuzumab, a first-in-class human epidermal receptor 2 (HER2) dimerization inhibitor, is a humanized monoclonal anti-HER2 antibody that binds HER2's dimerization domain and inhibits HER2 signaling. Based on supporting preclinical studies, we undertook a Phase II trial of pertuzumab in patients with recurrent non - small cell lung cancer (NSCLC). Experimental Design: Patients with previously treated NSCLC accessible for core biopsy and naive to HER pathway inhibitors were treated with pertuzumab i.v. once every 3 weeks. Tumor assessments were done at 6 and 12 weeks and then every 3 months thereafter. The primary efficacy end point was overall response rate by Response Evaluation Criteria in Solid Tumors. Measurement of tumor glucose metabolism (SUVmax) by F-18-fluorodeoxyglucose positron emission tomography was used as an exploratory pharmacodynamic marker of drug activity. Results: Of 43 patients treated with pertuzumab, no responses were seen; 18 of 43 (41.9%) and 9 of 43 (20.9%) patients had stable disease at 6 and 12 weeks, respectively. The median and 3-month progression-free survival rates (PFS) were 6.1 weeks (95% confidence interval, 5.3-11.3 weeks) and 28.4% (95% confidence interval, 14.4-44.2%), respectively. Of 22 patients who underwent F-18-fluorodeoxyglucose positron emission tomography, six (27.3%) had a metabolic response to pertuzumab as evidenced by decreased SUVmax. These patients had prolonged PFS (HR = 0.11, log-rank P value = 0.018) compared with the 16 patients who had no metabolic response. Four patients (9.3%) experienced a grade 3/grade 4 adverse event judged related to pertuzumab; none exhibited grade 3/grade 4 cardiac toxicity. Conclusions: Pertuzumab is well tolerated as monotherapy. Pharmacodynamic activity correlated with prolonged PFS was detected in a moderate percentage of patients (27.3%). Further clinical development of pertuzumab should focus on rational combinations of pertuzumab with other drugs active in NSCLC. ©2007 American Association for Cancer Research. |
| Keywords: |
adult; treatment outcome; aged; middle aged; mutation; clinical trial; drug tolerability; fatigue; erlotinib; diarrhea; drug efficacy; drug safety; monotherapy; antineoplastic agents; disease free survival; positron emission tomography; multiple cycle treatment; pharmacodynamics; phase 2 clinical trial; lung non small cell cancer; nausea; carcinoma, non-small-cell lung; lung neoplasms; epidermal growth factor receptor 2; receptor, epidermal growth factor; biopsy; time factors; docetaxel; drug hypersensitivity; drug receptor binding; dyspnea; antibodies, monoclonal; multicenter study; cardiotoxicity; fluorodeoxyglucose f 18; fluorodeoxyglucose f18; positron-emission tomography; gefitinib; dimerization; protein structure, tertiary; receptor, erbb-2; trastuzumab; lung biopsy; pemetrexed; lung infiltrate; pertuzumab; adult respiratory distress syndrome; glucose metabolism
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